RO115109B1 - Stable composition containing retinoid - Google Patents

Abstract

PCT No. PCT/NL94/00151 Sec. 371 Date Dec. 28, 1995 Sec. 102(e) Date Dec. 28, 1995 PCT Filed Jul. 1, 1994 PCT Pub. No. WO95/01160 PCT Pub. Date Jan. 12, 1995Compositions for topical application to the skin are provided, which compositions comprise a retinoid in an aqueous vehicle, and further contain at least one non-ionic surfactant, wherein the non-ionic surfactant is the crystallization-preventing and stabilizing agent for said retinoid and is selected from the group consisting of polyoxyethylene mono fatty alcohol ethers, polyoxyethylene glyceryl fatty acid triesters and ethyleneoxide/propyleneoxide block copolymers.

Description

The present invention relates to a stable composition with retinoid, pharmaceutical and cosmetic, for local application, on the skin.

Local compositions comprising a retinoid in an aqueous vehicle are known.

Vitamin A or retinoic acid, the name IUPAC 3,7-dimethyl-9- (2,6,6-trimethyl · 1-cyclohexane-1-yl) -2,4,6,8-nonatetraenoic acid, has been used locally, for the treatment of acne vulgaris and recently, for the treatment of skin aging. The naturally occurring form is entirely trans or tretinoin compound, but cis compounds are also known. Compound 13-cis or isotretinoin is also used as a keratolytic agent. Both isomers and their derivatives, such as salts, esters and amides, and structural analogues, such as ethretinate, belong to the retinoid group.

WO 90/14833 (Bazzano) discloses a stable aqueous composition for local application to the skin, comprising a retinoid. The composition may also comprise 0.1 ... 20% by weight of a solubilizing agent (ethanol) and a surface active agent, the latter ingredient being added to have a double benefit of helping to maintain the active ingredient in suspension. uniform in formulation, while improving the bioavailability of the active ingredient.

However, the stability of the compositions is still limited: Table II on page 17 mentions the percentage decomposition of tretinoin in 7 formulations, the percentage being 3 ... 13%, after 10 months of storage. Moreover, all examples have compositions comprising a substantial amount of ethanol as a solubilized agent. Thus, it is expected that the respective compositions will still cause skin irritation and inflammation, due to the presence of the respective solubilizing agent.

EP-A-393904 (Maxam) discloses a water-based, non-alcohol, oil or greasy formulation comprising tretinoin in an incomplete solvated form, a gelling agent. The formulation may also comprise one or more antioxidants, preservatives and glycerin. A surface agent, the choice of which does not appear to be critical, may also be incorporated into the formulation to allow good dispersion of the active ingredient and increase penetration into the skin. It is said that the compositions are physically and chemically stable. However, it is well known that protein materials, such as proteins, polypeptides, peptides, amino acids and mucopolysaccharides as mentioned herein, are prone to microbial attack and / or chemical degradation, especially in aqueous carriers. Therefore, the stabilizing effect exerted by the respective materials will be limited.

Additionally, reference is made to US patents 4022913 and 4532133, which describe both compositions comprising alcohol esters of vitamin A, for use as high potency vitamin preparations and additives for animal nutrition.

Retinoids are insoluble or are at most very poorly soluble in water, but are slightly soluble in ethanol for example. Therefore, retinoid-containing preparations were most effectively applied using an alcohol-containing solvent system, which in itself causes an unpleasant burning sensation. The sensation is amplified when the application is made to the skin that has been previously treated or is treated simultaneously with retinoic acid. Cream formulations have been found to be generally more acceptable to patients, but have been found to have other disadvantages, such as reduced clinical efficacy compared to alcoholic compositions containing the same amount of retinoic acid, and sometimes have the effect of fat-forming baskets. or oils used in formulations. Retinoic aqueous preparations containing no alcohol and fats have not been shown

EN 115109 Bl is too good for clinical efficacy because the active ingredient is not dissolved and thus not accessible to exert the desired effect.

The retinoid stable composition according to the invention consists of 0.001 - 0.5% retinoid, up to 5% organic solvent, 0.5 - 20% nonionic surfactant selected from: polyoxyethylene fatty alcohol monoethers, triesters with glyceryl polyoxyethylene fatty acid, ethylene oxide / propylene oxide copolymer mixture, optionally 0.01 - 4% antioxidants, 10% emollient, a substance from the antibiotic group, as well as pharmaceutically acceptable excipients, the ratios being expressed by weight; the nonionic surfactant is selected from: polyoxyethylene (4) monolauryl ether, 55 polyoxyethylene (25) glycerol triethylene, a liquid ethylene oxide / propylene oxide copolymer block containing 40% ethylene oxide and 60% propylene oxide and has a molecular weight of 2000-3000; another nonionic surfactant selected from the group of polyoxyethylene glycerin fatty acid monoesters; polyoxyethylene glycerin fatty acid monoester is polyoxyethylene (15) glycerol monolaurate; contains up to 0.1% by weight of organic solvent; 60 antibiotic is clindamycin or a derivative thereof.

The present invention provides a composition, comprising a retinoid in an aqueous carrier, containing at least one crystallization prevention agent and stabilizer, selected from the group of nonionic surface active agents.

The surface active agents are known per se and effectively the composition 65 according to the invention comprises a surface active agent selected from a polyoxyalkylene compound, a polyoxyalkylene polymer, a polyoxyalkylene polymer block or a mixture of two or more such substances. In general, the alkylene radical of the respective substances comprises from 2 to 5 carbon atoms, preferably 3 or 4 carbon atoms, in particular, the above nonionic surfactants are represented by 7o polyoxyethylene fatty alcohol ethers, acid triesters glyceryl polyoxyethylene, glyceryl and block copolymers ethylene oxide - propylene oxide. Highly suitable representatives of the above nonionic surfactants are polyoxyethylene (4] monolauryl ether, polyoxyethylene (25] glycerintrioleate and a liquid ethylene oxide / propylene oxide copolymer block containing 40% ethylene oxide and 60% propylene oxide and having molecular 3000 75 (Synperonic PE / L 44 ^R ).

In another advantageous embodiment, the composition of the invention further comprises a nonionic surfactant of the polyoxyethylene glycerine fatty acid monoester group, such as polyoxyethylene (15) glycerol monolaurate.

It has been found that the addition of at least one crystallization prevention agent and stabilization to compositions comprising a retinoid in an aqueous vehicle having a pH between 3 and 7, surprisingly leads to an improvement in the chemical stability of the active ingredient. This has been demonstrated in particular for compositions comprising a retinoid and a polyoxyethylene monoeter in an aqueous carrier, both after storage at elevated temperatures for several months and after storage at 85 ambient conditions for at least 18 months. months.

At the microscopic evaluation of the compositions according to the invention no active ingredient crystals were observed, as well as after storage for more than one year at room temperature. In order to increase the accessibility of the active ingredient and thus its clinical efficacy, an organic solvent, such as monohydrous C 1 -C 6 alkanol and in particular ethanol and / or isopropyl alcohol, must be incorporated into known compositions comprising retinoic acid. in compositions according to the present invention are not required

EN 115109 B substantial amounts of such an organic solvent, although it may be present in an amount of up to 5% by weight, preferably up to 1% by weight and especially in an amount of O - 0.1% in weight. An advantage of the compositions according to the present invention 95 is that the effect of extreme drying on the skin, due to the use of relatively large quantities of organic solvents in known compositions, has been avoided. Moreover, water-based compositions do not cause any problems related to environmental and safety issues.

The compositions of the present invention comprise a locally effective amount of a retinoid ointment and can be successfully used for the local treatment of vulgar acne and skin aging. However, other locally effective drugs may be incorporated, which may increase the therapeutic effect of the retinoid, without any adverse effect on clinical stability or efficacy. Examples of these are corticosteroids and antibiotics. Preferably, water-soluble antibiotics such as clindamycin phosphate or its hydrochloric acid addition salt are used. The combination products of retinoic acid and clindamycin phosphate according to the invention have proven to be particularly suitable for mixed forms of acne vulgaris: acne with baskets with mild to moderate inflammation. For this indication it is usually prescribed either a local preparation containing antibiotic or a local preparation containing tretinoin. It is sufficient to apply once a day non-combination products according to the invention.

The retinoid concentration in the composition can be in the range from 0.001 to 0.5% by weight, preferably from 0.01 to 0.1% by weight, and especially from 0.025 to 0.05% by weight.

As shown above, an advantageous group of nonionic surfactants is formed by polyoxyethylene monoethers such as polyoxyethylene (4) monolauryl ether. The latter product is also known as CTFA Laureth-4 and is accessible on the market under the brand name Brij 30 ^(R , Volpo L4 ^(R1 and Simulsol P4 ^(R)) .

Another advantageous group of non-ionic surfactants is the fatty acid triesters of glycerol polyoxyethylene such as polyoxyethylene (25) glycerol triethylene. 120 The last product is accessible on the market under the brand name Tagat T0 ^[R) . □ another advantageous group of nonionic surface active agents is formed by ethylene oxide / propylene oxide copolymer block; an example of the latter is Synperonic PE / L44 ^(R) .

The above products give, when incorporated in a composition according to the invention, good results expressed by stability and applicability. 125

Further improvements are found when in addition to the non-ionic surface active agents referred to, a product selected from the group of polyoxyethylene glycerin fatty acid monoesters is included. A typical representative thereof is polyoxyethylene (15) glycerol monolaurate which is accessible under the trade name Glycerox L15 ^(R1 .

The amount of non-ionic surface active agents to be added to 130 compositions depends on the amount and type of active ingredients used, but generally ranges from 0.5 to 20% by weight, preferably from 1 to 10% in weight and especially from 2 to 5% by weight. If a combination of polyoxyethylene monoether and a polyoxyethylene glycerine monoester is used, the molecular ratio of these compounds is between 10: 1 and 1: 1 (polyoxyethylene monoeter: polyoxyethylene monoester glycerine) and, if the combination of laureth-4- is selected, and 135 Glycerol polyoxyethylene- (15] -monolate, preferably about 2.5, However, it is also possible to use a mixture of representatives from each group of nonionics.

RO 115109 Bl

The viscosity of the aqueous carrier can be increased by the addition of known viscosity enhancing substances, such as cellulose derivatives such as hydroxypropyl cellulose and polyacrylic acids, such as those accessible under the trademark Carbopol.

The pH of the compositions is preferably adjusted by the addition of a physiologically acceptable buffering agent at a pH between 3 and 7, but preferably between 4.0 and 5.5.

Because the retinoid is sensitive to oxidation and decomposes in aqueous medium, the compositions of the present invention may also optionally contain an effective amount of one or more antioxidants at a concentration appropriate to the active ingredient, such as about 0.01 to 4% by weight of the composition. Due to the above combination of surface active agents, the effective concentration of antioxidants in known compositions containing retionic acid.

The compositions may contain up to about 10% emollient or non-irritating as an additional aid to avoid any skin drying effects that are an intrinsic property of the active ingredient. Examples of such emollients are C ₁₂ -C ₂₂ fatty alcohols and fatty acid esters, silicone oils and vegetable oils. Examples of non-irritants are the natural moisturizing factor, humectants, etc.

The compositions of the present invention may further comprise other suitable excipients, such as sequestrants, buffers and preservatives.

The compositions are preferably prepared according to procedures known in the art for the preparation of compositions containing compounds which can easily oxidize in the presence of light and / or oxygen. Due to the combination of surface agents mentioned above, it may not be necessary to completely exclude oxygen during the preparation of compositions of the present invention.

In a pilot clinical study, an aqueous composition according to the invention has been shown to be at least as effective as a commercially acceptable known composition comprising retinoic acid in an alcoholic carrier.

Therefore, there is thus a need to create a composition comprising a retinoid, a composition which:

- is physically and chemically stable;

- does not contain alcohol,

- is clinically at least as effective as the prior art composition, containing the respective retinoid in an alcoholic vehicle.

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Below are five examples of embodiments of the invention; Example 1 retionic acid 0.025% disodium age 0.10% butylhydroxytoluene 0.02% Carbopol ^(R) 980 1.0% laureth-4 2.0% tromethamine 0.75% citric acid monohydrate 0.15% propylene 7.5% methylhydroxybenzoate 0.1% water up to 100.0%

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RO 115109 Bl

The preparation method is as follows:

I Carbopol is added to a mixture of propylene glycol and water.

II Laureth-4 is heated to 35-40 ° C, followed by butyl hydroxytoluene, retinoic acid and methylhydroxybenzoate. The mixture is stirred until the components are completely dissolved, excluding oxygen, protected from the influence of light.

III Citric acid monohydrate and tromethamine are dissolved in water under stirring and heating up to 50 - 6 ° C.

While shaking, Phase II is first added to Phase I, and then Phase III is added, protected from light at a temperature of 50 - 6 ° C. The whole is placed under vacuum, shaken again, placed under vacuum and then cooled until the temperature drops below 3 ° C. Nitrogen is added and the product is removed from the ointment mixer.

Example 2. retinoic acid 0.025% clindamycin phosphate 1.20% disodium age 0.10% butylhydroxytoluene 0.02% Carbopol ^(R) 980 1.0% laureth-4 4.0% tromethamine 0.75% citric acid monohydrate 0.15% propylene 7.5% methylhydroxybenzoate 0.1% water up to 100.0% The gel is prepared according to the manufacturing process of Example 1; phosphate

clindamycin is dissolved in water together with citric acid monohydrate and tromethamine.

Example 3. Example 2 is repeated, but now instead of 4% Laureth 4 a mixture of 2% Laureth 4 (polyoxyethylene (4) monolauryl ether) and 2% Glycerol L15 ^(F (polyoxyethylene (15) glycerinmonolayer)) is used. get a product as good in terms of stability and applicability.

Example 4. Example 2 is repeated, but instead of 4% Laureth-4 4% is used with either Synperonic PE / L44 ^(R) or Tagot TO ¹ ™. An equally good product is obtained in terms of stability and applicability.

Tests have been performed that demonstrate the effectiveness of the composition:

Example 5

A multi-center pilot study with a double blind sample, incidentally, is performed on 40 patients with moderate to severe acne vulgaris grade 3 or higher for the Cook measurement scale to compare the effectiveness of the known composition containing 0.025% by weight retinoic acid in an alcoholic gel carrier, and of the composition according to the present invention (aqueous gel of Example 2).

The medication was applied once daily in the evening to acne lesions for a period of 12 weeks.

Both treatment groups responded to therapy. Patients treated with the composition of Example 2 have a faster response and the number of lesions inflamed after 12 weeks is significantly lower than in patients treated with alcoholic retinoic acid gel. The treatment groups were shown to be comparable to non-inflamed lesions,

Although it can be shown a numerical difference in favor of compositions according to the present invention.

Claims (6)

claims 1. Retinoid stable composition, for local administration, based on retinoid, characterized in that it consists of 0.001 - 0.5% retinoid, up to 5% organic solvent, 0.5 - 20% non-ionic surfactant selected from: polyoxyethylene fatty alcohol monoethers, glycerol polyoxyethylene fatty acid triesters, ethylene oxide / propylene oxide copolymer mixture, optionally 0.01 - 4% antioxidants, 10% emollient substance, a substance from the antibiotic group, as well as pharmaceutically acceptable excipients, being expressed in weight. A stable retinoid composition for local administration according to claim 1, characterized in that the nonionic surfactant is selected from: polyoxyethylene (4) monolauryl ether, polyoxyethylene (25) glycerol triethylene, an ethylene oxide / propylene oxide liquid copolymer block containing 40 % ethylene oxide and 60% propylene oxide and has a molecular weight of 2000-3000. 3. Retinoid stable composition for local administration according to claim 1 or 2, characterized in that it comprises another non-ionic surface active agent selected from the group of polyoxyethylene glycerol fatty acid monoesters. A stable retinoid composition for local administration according to claim 3, characterized in that the polyoxyethylene glycerin fatty acid monoester is polyoxyethylene (15) glycerol monolaurate. 5. Retinoid stable composition for local administration according to claims 1 to 4, characterized in that it contains up to 0.1% by weight of organic solvent. 6. Retinoid stable composition for local administration according to claim 1, characterized in that the antibiotic is clindamycin or a derivative thereof.